Effects of Virtual Reality on the Limb Motor Function, Balance, Gait, and Daily Function of Patients with Stroke: Systematic Review

Background and Objectives: This systematic review aimed to clarify the effectiveness of virtual reality rehabilitation on physical outcomes for people with stroke. Materials and Methods: Articles were searched through PubMed, EMBASE, the Cochrane Library, the Physiotherapy Evidence Database, CINAHL, Web of Science, and ProQuest Dissertations and Theses, from inception to 30 April 2022. Methodological quality was scored using the Assessing the Methodological Quality of Systematic Reviews 2 tool. Each systematic review for the outcome of interest was assessed by two independent reviewers using the Grading of Recommendations Assessment, Development, and Evaluation system. Results: Twenty-six articles were selected. These studies evaluated the effectiveness of virtual reality on limb motor function, balance, gait, and daily function in patients with stroke. The findings suggested a beneficial effect of virtual reality; there was a “very low” to “moderate” quality of evidence for improved limb extremity function, balance, and daily function, and a “very low” to “moderate” quality of evidence for improved gait. Conclusions: Despite widespread interest in the use of virtual reality rehabilitation, high-quality evidence for its routine use in stroke treatment is lacking. Further research is needed to determine the treatment modality, duration, and long-term effects of virtual reality on stroke populations.


Introduction
Stroke is the second leading cause of disability and death worldwide. In 2019, 12.2 million stroke events were reported, and the prevalence of stroke was 101 million [1]. Stroke is the main cause of cognitive deficits [2], and most stroke survivors suffer from long-term functional impairment. Current evidence suggests that most patients with cerebrovascular diseases with upper or lower limb injuries have persistent difficulties in dealing with the challenges of daily life, for instance, falls due to gait and balance problems [3]. Damage to the cerebral cortex affects patients' physical function and motion ability and their quality of life [4].
Rehabilitation training can effectively improve the limb activity function of stroke patients, and reduce the rate of disability [5]. Traditional rehabilitation therapy relies heavily on physiotherapy and occupational therapy. Repetitive and task-specific exercises lead to controversy regarding the compliance and cost-effectiveness of traditional rehabilitation therapy, and its space and time constraints; the rehabilitation effect is highly related to the skills of the physical therapists, and traditional rehabilitation therapy cannot fully meet the needs of patients [6,7].
Virtual reality (VR) is achieved through computer hardware and software, whereby interactive simulations created by a computer provide participants with virtual environments similar to actual objects and events [8]. VR has been introduced as a potential The methodologies included in this review were assessed using the Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR-2) tool [16]. AMSTAR 2 contains 16 items, among which items 2,4,7,9,11,13, and 15 are the critical domains. If the answer to the item is correct and well-founded, then the judgment is "Yes"; if the answer to the item is correct but not well-founded, then the judgment is "partial Yes"; if the entry has no relevant evaluation information, then the judgment is "No". Methodologies with no or one noncritical weakness(es) were rated "High"; those with more than one noncritical weakness were rated "Moderate"; those with one critical flaw with or without noncritical weaknesses were rated "Low"; and those with more than one critical flaw with or without noncritical weaknesses were rated as "Critically Low".
In terms of quality of evidence, each systematic review of the outcomes of interest was assessed by two independent reviewers (B. Zhang and K.P. Wong) using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system [17]. The GRADE system was based on five lower factors. The quality of evidence was rated "High", "Moderate", "Low", or "Very Low". The quality of evidence rating for randomized controlled trials (RCTs) was preset as "High", downgraded by 1 to "Moderate", downgraded by 2 to "Low", and downgraded by 3 to "Very Low". All disagreements were resolved by three researchers (B. Zhang, K.P. Wong, and J. Qin).

Data Synthesis
The characteristics of the included systematic reviews were described in a narrative manner. Differences in the participants, interventions, and types of data analysis in each review, and the main outcomes, were considered when assessing the effects of the interventions. Wherever possible, a summary of the results and of the statistical analyses for each included review is provided in summary tables and figures. More than one eligible review was found for VR and conventional rehabilitation. Common findings were reported when the reviews had similar conclusions, and the reasons for any differences related to the AMSTAR scores and the differences in participants, interventions, and type of data analysis included in the reviews were explored when the findings differed. Overlap in the trials included in the reviews that evaluated similar interventions was expected. In this case, the results were compared across all reviews and collapsed wherever possible.

Search Results
A total of 891 studies were initially retrieved, and three reviews were determined by manually searching the references of related articles. After 454 duplicate articles were excluded, the title abstracts were read to exclude irrelevant literature. After further reading of the full texts, 26 systematic reviews were finally included. The PRISMA flow diagram of the study selection process is shown in Figure 1.

Data Synthesis
The characteristics of the included systematic reviews were described in a narrative manner. Differences in the participants, interventions, and types of data analysis in each review, and the main outcomes, were considered when assessing the effects of the interventions. Wherever possible, a summary of the results and of the statistical analyses for each included review is provided in summary tables and figures. More than one eligible review was found for VR and conventional rehabilitation. Common findings were reported when the reviews had similar conclusions, and the reasons for any differences related to the AMSTAR scores and the differences in participants, interventions, and type of data analysis included in the reviews were explored when the findings differed. Overlap in the trials included in the reviews that evaluated similar interventions was expected. In this case, the results were compared across all reviews and collapsed wherever possible.

Search Results
A total of 891 studies were initially retrieved, and three reviews were determined by manually searching the references of related articles. After 454 duplicate articles were excluded, the title abstracts were read to exclude irrelevant literature. After further reading of the full texts, 26 systematic reviews were finally included. The PRISMA flow diagram of the study selection process is shown in Figure 1.

Study Characteristics
A total of 26 systematic reviews involving 22,031 adult participants with post-stroke disorders were included, and one of these reviews did not report the number of participants. This study identified 22 papers comprising systematic reviews and meta-analyses and 4 papers comprising systematic reviews only. The age range of participants was 18-94 years, and eight studies reported the sex of participants, with 5350 males and 3400 females.
Nine systematic reviews (n = 8740 participants) evaluated the effectiveness of VR on upper extremity functional recovery. Lower extremity functional recovery was reported in three systematic reviews (n = 1124), limb function (upper and lower extremity) was evaluated in five systematic reviews (n = 7255), the effectiveness of VR on balance function

Study Characteristics
A total of 26 systematic reviews involving 22,031 adult participants with post-stroke disorders were included, and one of these reviews did not report the number of participants. This study identified 22 papers comprising systematic reviews and meta-analyses and 4 papers comprising systematic reviews only. The age range of participants was 18-94 years, and eight studies reported the sex of participants, with 5350 males and 3400 females.
Nine systematic reviews (n = 8740 participants) evaluated the effectiveness of VR on upper extremity functional recovery. Lower extremity functional recovery was reported in three systematic reviews (n = 1124), limb function (upper and lower extremity) was evaluated in five systematic reviews (n = 7255), the effectiveness of VR on balance function was reported in seven systematic reviews (n = 5356), gait was reported in five systematic reviews (n = 5019), and daily living skills were assessed in four systematic reviews (n = 5073).
Fourteen systematic reviews performed subgroup analyses regarding time since the onset of stroke, the intervention method, the type of VR, VR intervention duration, the frequency of intervention, control group type, the severity of paresis, outcomes, and study quality. The basic characteristics and a reference list of the included systematic reviews are shown in Table 2.

Quality of the Systematic Reviews
Among the 26 systematic reviews, 1 was rated "High", 5 were rated "Moderate", 14 were rated "Low", and 6 were rated "Critically Low". All 26 systematic reviews comprehensively searched the database, and seven of them also searched the grey databases and references in the included literature. All 26 systematic reviews reported the included studies' basic characteristics and a list of excluded literature, and used appropriate bias tools to conduct a risk assessment. Among the 26 systematic reviews, 16 used The Physiotherapy Evidence Database scale, 7 used the Cochrane risk of bias tool, and 1 used The Downs and Black scale and the CONSORT checklist, the Jadad scale, and the ROBINS-2 tool. However, none of the 26 systematic reviews reported the reasons for the selection of RCTs and the funding of the original studies. Seven systematic reviews completed the registration of research methods ahead of schedule. Only one systematic review did not consider the effect of risk of bias on the results in its discussion. Given that four systematic reviews were only qualitative evaluations, no publication bias analysis was carried out. Among the remaining 22 meta-analyses, only seven analyzed publication bias. Table 3 demonstrates the results of the AMSTAR-2 quality evaluation.
The overall quality of the evidence for VR rehabilitation was assessed using the GRADE system (Table 4). Owing to the specific nature of this therapy, all included systematic reviews were at risk of bias in terms of blinding. Table 5 shows a synthesis of the best evidence on VR rehabilitation for patients with stroke.

Evidence Synthesis of Upper Limb Function
Fourteen systematic reviews assessed the outcome of VR in the rehabilitation of upper extremity motor function among patients with stroke. The results of 10 systematic reviews indicated that VR rehabilitation was more effective than traditional training in restoring upper limb function in stroke patients. Al-Whaibi et al. [22] and Laver et al. [8] suggested that VR rehabilitation training was effective but not statistically significant compared with conventional rehabilitation training. The study of Khan et al. [19] was divided into two parts: qualitative synthesis, which suggested that VR rehabilitation was effective, and meta-analysis, which showed that the comparison of Fugl-Meyer scores was not statistically significant.

Evidence Synthesis of Lower Limb Function
Eight systematic reviews summarized the VR rehabilitation results for lower limb function in stroke patients. Corbetta et al. [38] indicated that patients with stroke demonstrated the effectiveness of limb function recovery only when they received VR intervention combined with conventional training. However, Laver et al. [8] found that the use of VR for rehabilitation in addition to usual nursing did not have a significant influence on patients' motor function.

Evidence Synthesis of Balance
Balance was reported in seven systematic reviews, all of which concluded that VR could provide better balance in stroke patients compared with conventional rehabilitation. After further analysis, VR rehabilitation was found to be more effective in the chronic phase in patients with stroke than in the acute phase (95% CI: 0.03-0.53, p = 0.03). Three studies found that the combination of traditional rehabilitation with VR could significantly improve the balance ability of patients, and is better than conventional rehabilitation alone. Iruthayarajah et al. [35] also observed that postural VR was better for balance function than other types of VR.

Evidence Synthesis of Gait
Five studies reported gait, all of which confirmed that VR significantly improved walking speed and cadence in patients with stroke. Zhang et al. [20] found that a minimum of 5 weeks of VR intervention was needed for great improvements in gait and self-care in daily life (95% CI: 7.63-17.64, p < 0.001). Rooij et al. [13] stated that VR combined with conventional therapy and time-dose matching was more effective for training gait than conventional training (95% CI: 0.38-1.69, p = 0.002).

Evidence Synthesis of Daily Function
Four systematic reviews reported the results of daily function. Only Aminov et al. [32] concluded that the rehabilitation effect of VR was consistent with that of conventional rehabilitation in terms of daily activities. Hence, their results were not considered significant. The remaining studies suggested that VR can better improve daily function than conventional rehabilitation.

Evidence Synthesis of Subgroup Analysis
Through subgroup analysis, Laver et al. [8] pointed out that VR plus traditional rehabilitation training was highly beneficial for upper limb recovery. The same results were obtained by Fang et al. [24] and Li et al. [23]. Mekbib et al. [25] indicated that VR rehabilitation was highly effective in improving upper limb function in patients with subacute stroke. However, Al-Whaibi et al. [22] found that VR intervention can effectively improve upper limb function in subacute stroke and in the chronic phase of stroke. Fang et al. [24] found that immersive VR devices were better for rehabilitation than non-immersive VR. In addition, the duration and dose of VR were reported. Two systematic reviews found that a minimum of 10 sessions should be received by patients to ensure that the treatment is useful [8,24]. Laver et al. [8] and Mekbib et al. [25] noted that in VR training with an intervention duration of more than 15 h, the intervention group showcased great improvements in upper limb dysfunction and activity limitation compared with the control group. Li et al. [23] revealed that VR sessions lasting longer than 45 min for less than 6 weeks are highly beneficial to structure/function. Lee et al. [29] found that VR rehabilitation required a minimum of 5 weeks to improve the daily abilities of patients.
The overall results of this systematic review of the use of VR in stroke patients suggest "Very Low" to "Moderate" evidence quality for improved upper extremity function after stroke; "Very Low" to "Moderate" evidence quality for improved lower extremity function after stroke; "Very Low" to "Moderate" evidence quality for improved balance after stroke; "Very Low" and "Moderate" evidence quality for improved gait after stroke; and "Very Low" to "Moderate" evidence quality for improved daily function after stroke.

Discussion
This systematic review is the first study to comprehensively evaluate systematic reviews of VR's efficacy in stroke patients. Twenty-six systematic reviews (758 RCTs with 22,031 participants) were included to summarize the best and latest evidence of the effectiveness of stroke rehabilitation interventions. This systematic approach to assessing review outcomes allows us to conduct a comparison of results from multiple reviews, providing a comprehensive evidence-based summary of the results. Our findings suggest beneficial effects of VR in improving limb function, balance, gait, and daily function, but the quality of evidence is low.
VR provides real-time multisensory feedback such as visual, auditory, and haptic feedback [42], and tracks patient performance and training details, such as the type and intensity of exercise [43]. The characteristics of VR make most RCTs unsuccessful in blinding participants and conductors, resulting in low-quality evidence. In addition, the systematic reviews included in this study involved different ethnicities and regions, resulting in high heterogeneity and the risk of inconsistent bias in quality assessment, which is one of the reasons for the low-quality evidence.
This study found that VR can successfully enhance the upper and lower limb function, balance, gait, and daily function of patients with stroke; however, high-quality evidence is severely lacking. VR positively affected functional recovery processes in patients with stroke, including pain reduction, muscle strengthening, and sensation recovery [29]. Lee et al. [44] used VR to intervene in the balance function of patients with stroke, and found that VR games had a positive effect on the balance of patients with stroke, who experienced greater pleasure during the intervention than during the standard treatment. Furthermore, VR improves the neural plasticity of patients with stroke by allowing them to perform functional task-specific activities in an enriched environment [5,45]. The high task variability, flexibility, and specificity of VR successfully boost patients' motivation to comply with the therapeutic training [46]. Intensive therapy, the use of games to complete rewarding therapy, stimulus learning, and constructive feedback between stimulus and response are four components that can work together to ensure success through VR therapy [47].
Exercise intensity is a key factor in meaningful training after a stroke. This study found that VR requires at least 5-8 weeks, and a total time of more than 15 h of rehabilitation to improve upper extremity function, gait cadence, and self-care in the lives of patients with stroke. Stroke patients take some time to adjust to VR programs, it is crucial that patients undergo at least 8 weeks of VR training for adaptability [22]. Meanwhile, the recovery of patients' structure/function was more evident when the session duration of VR exceeded 45 min compared with conventional therapy. This finding was identical to the recommendations for rehabilitation outlined in the national clinical guidelines for stroke in the United Kingdom [48]. Patients who received 45 min of daily upper extremity VR rehabilitation after a stroke experienced significant improvements in upper extremity function [49]. Moore et al. [50] implemented high-intensity rehabilitation training for 45-60 min per day in hospitalized patients with stroke, and found that the patients' lower limb function and balance ability were significantly improved. However, none of the studies we included performed subgroup analyses of intervention frequency with VR effectiveness. By performing a pooled analysis of intervention frequency across all the included studies, we found 3-5 interventions per week to be an appropriate frequency. Further studies are needed in the future to validate this finding.
Using immersive VR technology, Mekbib et al. [51] found effective recovery of active motor function in patients with stroke. Since fully immersive VR brings participants into a 360 • VR environment via a stereoscopic head-tracking head-mounted display, it provides effective treatment for impaired patients by enhancing the realism of experiencing another world [52]. This may be the reason why immersive VR is more effective than non-immersive VR.
This study was performed strictly in accordance with the PRISMA guidelines; however, some limitations may have influenced the results. First, although this study conducted a comprehensive search, only published studies were included, which may have led to selection bias. Second, due to the incompleteness of the included studies, this study did not summarize and analyze the follow-up data or the incidence of adverse effects of VR rehabilitation. Hence, the continuous effect and safety of VR rehabilitation cannot be determined. Given that this study focused on stroke patients' limb motor function, balance, gait, and daily function outcomes, it did not include and analyze the effects of VR on the cognitive domain. With the increasing number of systematic reviews being published, an overlap in RCT data in the included systematic reviews may occur, leading to bias due to the inclusion of the same outcome data. However, according to the Cochrane Handbook [14], this overview presented and described the physical outcomes of stroke patients under VR intervention and summarized them without further data analysis, so the results are acceptable. Finally, although the selection and quality assessment of studies were carried out independently by two researchers with group consensus, the included studies were of low quality. Caution should be taken when interpreting the results of this systematic review.

Conclusions
With the development of technology, the role of VR rehabilitation in patients with stroke has received increasing awareness. Our review suggests that VR exercise for a duration of 5-8 weeks, with a session frequency of 3-5 days/week, for 45 min/day, and with a total time of more than 15 h can make this intervention very effective, although the quality of evidence that VR can effectively improve limb motor function, balance, gait, and daily function in patients with stroke is low. Owing to the unsatisfactory quality of the included studies and the lack of methodologically reliable trials, additional high-quality RCTs are needed in the future to prove the rehabilitation effects of VR and to further clarify its treatment modality, duration, and frequency for application as a complementary strategy for conventional rehabilitation.